Phenyl-alkanolamine, alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants

ABSTRACT

Novel substituted 1-phenyl-2-alkylamino-alkanols, 1-phenyl-2-alkylamino-alkanes and α-aminoalkyl phenyl ketones useful as heart stimulants are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 443,034 filedFeb. 15, 1974 and now U.S. Pat. No. 3,976,783 which is a division ofapplication Ser. No. 160,529 filed July 7, 1971 and now U.S. Pat. No.3,816,516.

BACKGROUND OF THE INVENTION

This invention relates to alkanolamine, alkylamine and aminoalkylketoderivatives having useful therapeutic properties. It is particularlyconcerned with novel substituted 1-phenyl-2-alkylaminoalkanols,1-phenyl-2-alkylaminoalkanes and α-aminoalkyl phenyl ketones which areβ-agonists, i.e. stimulate the β-adrenergic receptors. In particular,these compounds increase the force of myocardial contraction, and areuseful in the curative or prophylactic treatment of cardiac conditionssuch as congestive heart failure. By virtue of their β-receptorstimulating properties these compounds are also useful in the treatmentof obstructive airways disease and peripheral vascular disease.

SUMMARY OF THE INVENTION

The compounds of the invention are those having the general formula:##STR1## wherein R and R¹ are each hydrogen or hydroxy with the provisothat at least one is hydroxy; R² is hydrogen, alkyl of from 1 to 4carbon atoms or alkoxy of from 1 to 4 carbon atoms; R³ is acylamino,alkoxycarbonylamino of from 1 to 4 carbon atoms, amoyl or ureido, anyone of which may be separated from the phenyl ring by a methylene orethylene group; R⁴, R⁵, and R⁶ are each hydrogen or alkyl of from 1 to 4carbon atoms; X is oxygen, sulfur, imino or a direct link; Y is hydrogenand hydroxy, two hydrogens or oxygen; n is 1 to 3 when X is other than adirect link and is 0 to 4 when X is a direct link; and the carboxylicacid esters and aldehyde condensation products of such a compound andthe pharmaceutically-acceptable acid addition salts.

In this specification "halogen" comprises fluorine, chlorine, bromineand iodine; "imino" group indicates the group --NR⁷ -- where R⁷represents hydrogen or a lower alkyl group; and the term "lower" used toqualify an alkyl or alkoxy group, indicates that such group contains upto 4 carbon atoms.

The aldehyde condensation products of the compounds of the invention areoxazolidines, having the formula: ##STR2## which are formed bycondensation of compounds of the invention in which R⁶ is hydrogen and Yrepresents a hydrogen atom and a hydroxy group with an aldehyde of theformula R⁸ CHO, where R⁸ is hydrogen or a lower alkyl group.

DETAILED DESCRIPTION OF THE INVENTION

In the above formulae, when R³ is amoyl, it may be a carbamoyl orsulfamoyl group having the formula --CO.NR⁹ R¹⁰ or --SO₂.NR⁹ R¹⁰,respectively, where R⁹ and R¹⁰ are each hydrogen or a lower alkyl or anaryl group or, together with the nitrogen atom to which they areattached, form a heterocyclic group, e.g. a pyrrolidino, piperidino,piperazino or morpholino group. When such a group is separated from thephenyl ring by a methylene or ethylene group, R³ has the formula --CH₂CONR⁹ R¹⁰, -- CH₂ CH₂ CONR⁹ R¹⁰, -- CH₂ SO₂ NR⁹ R¹⁰ or --CH₂ CH₂ SO₂ NR⁹R¹⁰.

When R³ is an acylamino group, it may be derived from the amide of acarboxylic or sulfonic acid, i.e. it may have the formula R¹¹ R¹² N--where R¹¹ is an acyl group derived from either a carboxylic or asulfonic acid, R¹² is hydrogen or a lower alkyl group, or R¹¹ and R¹²together with the nitrogen atom form a cyclic imido group. Moreover anysuch group may be separated from the phenyl ring by a methylene orethylene group, in which case R³ will have the formula R¹¹ R¹² NCH₂ --or R¹¹ R¹² NCH₂ CH₂ --.

Thus R³ may be, for example, a formamido, acetamido, propionamido,acrylamido, cyclo-hexane carbonamido, benzamido, furamido, phenylacetamido, methane sulfonamido, benzene sulfonamido group, or asubstituted derivative thereof, e.g. a chloroacetamido,trifluoracetamido, glycolamido, phenoxyacetamido, toluamido,nitro-benzamido, chlorobenzamido or toluene sulfonamido group, or acorresponding amido-methyl or 2-amido-ethyl group, e.g. anacetamido-methyl or 2-acetamido-ethyl group. When R¹¹ R¹² N-- is acyclic imido group, it may be derived from an aliphatic or aromaticdicarboxylic acid; thus R³ may be, for example, a succinimido, maleimidoor phthalimido group or a corresponding imidomethyl or 2-imido-ethylgroup.

When R³ is a ureido group, it may be ureido substituted with one or morelower alkyl groups on one or both of the nitrogen atoms. Thus it may be,for example, a 3-methyl ureido group.

Acids from which pharmaceutically-acceptable addition salts of thecompounds of the invention can be prepared are those which formnon-toxic addition salts containing pharmaceutically-acceptable anions,such as the hydrochloride, hydrobromide, hydroiodide, sulfate orbisulfate, phosphate or acid phosphate, acetate, maleate, fumarate,lactate, tartrate, citrate, gluconate, saccharate, and p-toluenesulfonate salts.

The compounds of the invention may be prepared in a number of ways: (1)An amine of the formula: ##STR3## is reacted with an aldehyde or ketoneof the formula: ##STR4## to give the corresponding Schiff's base, whichis reduced in the presence of a hydrogenation catalyst, e.g. platinum,to a compound of the invention in which R⁶ is hydrogen and Y representsa hydrogen atom and a hydroxy group.

After filtration and evaporation to dryness the product is isolated bytrituration followed by crystallization, or by dissolution in a suitablesolvent and precipitation as a salt, e.g. the hydrochloride, maleate,fumarate or oxalate, by addition of the appropriate acid.

(2) A phenacyl halide of the formula: ##STR5## where Z is halogen andR¹³ and R¹⁴ are each represent hydrogen or, a group PO--, where P is aneasily hydrogenolyzable protecting group, e.g. a benzyl group, at leastone of R¹³ and R¹⁴ being a group PO--, is reacted with an amine of theformula: ##STR6## to give a compound of the formula: ##STR7## To obtaina compound of the invention in which Y represents a hydrogen atom and ahydroxy group and R⁶ represents hydrogen, the ketonic compound isreduced to the corresponding secondary alcohol and the protecting groups(P) are removed by hydrogenolysis using a catalyst, e.g. palladium. Toproduce a compound of the invention in which Y represents an oxygen atomand R⁶ represents hydrogen, the ketonic compound itself is freed of theprotecting groups (P) by hydrogenolysis. The methods of isolation andpurification are similar to those given for method (1).

(3) An amide of the formula: ##STR8## in which R¹³, R¹⁴ and P are asdefined in (2) above, is reacted with a halo-compound of the formula:##STR9## in which Z is halogen, to give a compound of the formula:##STR10## The protecting groups (P) are then removed by hydrogenolysisas before and the methods of isolation and purification are similar tothose given for method (1).

(4) An amine of the formula: ##STR11## in which the single hydroxy groupis in either the 3- or the 4- position, is reacted with a halo-compoundof the formula (IX) to give a compound of the formula: ##STR12## Themethods of isolation and purification are similar to those given formethod (1). Where R⁶ is hydrogen, an excess amount of the amine is usedto prevent excessive formation of the tertiary amine by-product notrequired.

(5) The compounds of the invention in which R³ represents an acylamino,a lower alkoxy carbonylamino or a ureido group attached directly to thephenyl ring, i.e. groups wherein the free valency is on the nitrogenatom, R⁶ represents a hydrogen atom, and Y represents a hydrogen atomand a hydroxy group or an oxygen atom, may be prepared from a phenacylhalide of the formula (V) as defined in method (2) and an amine of theformula: ##STR13## to give a compound of the formula: ##STR14## For thepreparation of compounds wherein Y represents a hydrogen atom and ahydroxy group, the ketonic compound is then reduced to the correspondingsecondary alcohol, whereas for the preparation of compounds wherein Yrepresents an oxygen atom, this stage is omitted. The nitro group isreduced by hydrogenation in the presence of a catalyst, e.g., Raneynickel, to an amino group to give a compound of the formula: ##STR15##in which Y represents a hydrogen atom and a hydroxy group or an oxygenatom. The compound (XV) is then reacted with a suitable reagent forconversion of the amino group to an acylamino group, a loweralkoxycarbonylamino group or a ureido group; e.g. for conversion of theamino group to a formamido, ethoxycarbonylamino or a 3-methyl-ureidogroup, suitable reagents are formic acid, ethyl chloroformate andmethylisocyanate respectively. Finally, the protecting groups (P) areremoved by hydrogenolysis using a catalyst, e.g. palladium, to give acompound of the formula (I) wherein R³ represents an acylamino, a loweralkoxycarbonylamino or a ureido group attached directly to the phenylring, and Y represents a hydrogen atom and a hydroxy group or an oxygenatom.

(6) The compounds of the invention in which R³ represents an acylamino,a lower alkoxycarbonylamino or a ureido group attached directly to thephenyl ring, and Y represents two hydrogen atoms, may be prepared froman amine of the formula (VIII) as defined in method (3) and ahalo-compound of the formula: ##STR16## to give a compound of theformula: ##STR17## The nitro group is then reduced by hydrogenation inthe presence of a catalyst, e.g. Raney nickel, to an amino group to givea compound of the formula: ##STR18## The compound (XVIII) is thenreacted with a suitable reagent for conversion of the amino group to anacylamino, a lower alkoxycarbonylamino or a ureido group such as areexemplified in method (5). Finally, the protecting groups (P) areremoved by hydrogenolysis using a catalyst, e.g. palladium.

(7) The compounds of the invention in which R⁶ represents a lower alkylgroup may be prepared by the methods (2), (3), (5) and (6), but with theprotecting groups (P) attached to the nitrogen atom in the startingmaterials (VI), (VIII), (XIII) and (VIII) respectively, replaced by R⁶.

(8) The aldehyde condensation products of the compounds of the inventionmay be prepared by reacting a compound of the invention in which R⁴ andR⁶ are each hydrogen with an aldehyde of the formula R⁸ CHO, where R⁸ ishydrogen or a lower alkyl group, in a diluent or solvent, e.g. ethanol,preferably in the presence of an acid catalyst, e.g. hydrochloric oracetic acid, and preferably at an elevated temperature. The water formedin the reaction may be removed by azeotropic distillation by means of anentraining solvent, e.g. benzene, or by dehydrating agent, e.g.anhydrous potassium carbonate.

In the general methods (5) to (8), the methods of isolation andpurification are similar to those given for method (1).

Those compounds of the invention in which Y represents a hydrogen atomand a hydroxy group exist in D- and L-optically active isomeric formsand the invention includes these forms as well as the racemic mixtures.Method (1) described above may be used to prepare the optically activeisomers by using the appropriately substituted phenyl-ethanolamineenantiomer as starting material, whereas methods (2) and (5) applied tosuch compounds of the invention will result in the production of aracemic mixture. Alternatively, the racemic product of each of the abovemethods may be resolved by well-known techniques, e.g. by fractionalcrystallization of an addition salt formed with an optically activeacid.

Compounds in which R⁴ and/or R⁵ are other than hydrogen have more thanone asymmetric center and exist as two or more racemic pairs ofdiastereoisomers. In general, the products of the above methods will bea mixture of the pairs of stereoisomers, and these pairs may usually beseparated from each other by physical methods, e.g. by fractionalcrystallization or chromatography of the free bases or suitable salts.The invention includes the separated pairs, as well as mixtures thereof,as racemic mixtures or as separated D- and L-forms.

The activity of compounds of the invention as β-adrenergic stimulantsfor the heart has been shown by their effectiveness in one or more ofthe following tests: (a) increasing the force of contraction of theisolated electrically driven guinea-pig left atrium, and of isolatedelectrically driven cat papillary muscle; (b) increasing the forceand/or rate of contraction of spontaneously beating guinea-pig atria;(c) increasing cardiac output in the anaesthetized cat with an implantedleft ventricular catheter; (d) increasing cardiac output in theconscious dog with an implanted left ventricular catheter.

In test (a), the increased contractility of the muscle in response tothe test compound is measured in two animal species (guinea-pig andcat). The experiments are then repeated in the presence of a β-receptorblocking agent and on reserpinized atria to determine whether the testcompound is a directly acting β-receptor agonist.

In test (b) any selective action of compounds of the invention is showncompared with the catecholamines, noradrenaline and adrenaline, i.e.whether or not they increase the force of atrial contraction to agreater extent than the rate.

In test (c) the inotropic action of the test compounds followingintravenous administration is measured in the anaesthetized cat. Theperipheral effects of the compounds (e.g. effect on blood pressure) arealso measured in this preparation.

In test (d) the inotropic action of the test compound following oraladministration to a dog with an implanted left ventricular catheter ismeasured.

By virtue of their performance in tests (a) to (d), the preferredcompounds are to be found generally in those compounds of the inventionin which R represents hydrogen, R¹ represents a hydroxy group, R⁶represents hydrogen, X represents oxygen, Y represents a hydrogen atomand a hydroxy group, and n is 1. More particularly, the preferredcompounds have the above features and in addition R⁴ and R⁵ eachrepresent hydrogen. Particularly preferred compounds are those whichshow good potency of activity in test (a), and which show a goodinotropic response and good duration of action accompanied by only aslight increase in heart rate in test (c), and are specificallyDL-2-[2-(4-carbamoylphenoxy)ethylamino]-1-(4-hydroxyphenyl) ethanol,DL-1-(4-hydroxyphenyl)-2-[2-(4-{3-methylureido}phenoxy)ethylamino]ethanol andDL-2-[2-(4-formamidophenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol. Twomore compounds,DL-2-[2-(4-carbamoylmethylphenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanoland DL-2-[2-(4-acetamidophenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanolhydrochloride show good potency of activity in test (a), but areinferior to the three particularly preferred compounds in test (c).

The compounds of the invention can be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they may be administeredorally in the form of tablets containing such excipients as starch orlactose, or in capsules either alone or in admixture with excipients, orin the form of elixirs or suspensions containing flavoring or coloringagents. They may be injected parenterally, for example, intramuscularlyor subcutaneously. For parenteral administration, they are best used inthe form of a sterile aqueous solution which may contain other solutes,for example, enough salts or glucose to make the solution isotonic.

In general, the compounds of the invention are administered in dosagesof from about 0.5 to about 20 mg./per kg. of body weight per day takenorally in three of four divided doses. Dosages for intravenousadministration are about one-tenth of the above dose in a single doseper day.

EXAMPLE I

A mixture of DL-octopamine (4.6 g.), 4-carbamoylphenoxy acetone (5.8 g.)and ethanol (150 ml.) was boiled under reflux for 8 hours in thepresence of molecular sieves, then hydrogenated over platinum oxide at50 p.s.i. and 50° C. Filtration and evaporation in vacuo of the filtrategave a viscous oil which was triturated with ether to provide asemi-solid material. This material was then triturated with ethanol andthe residual white solid crystallized from aqueous dimethylformamide toaffordDL-2-[2-(4-carbamoyl-phenoxy)-1-methylethylamino]-1-(4-hydroxyphenyl)ethanolhemihydrate (2.0 g.), m.p. 195°-198° C.

Analysis: Calc'd. for C₁₈ H₂₂ N₂ O₄.0.5H₂ O: C, 63.70; H, 6.83; N,8.26%: Found: C, 63.98; H, 6.37; N, 8.27%.

EXAMPLE II

Also prepared by the method described in Example I from DL-octopamineand 2-carbamoyl-4-methylphenoxy acetone wasDL-2-[2-(2-carbamoyl-4-methylphenoxy)-1-methylethylamino]-1-(4-hydroxyphenyl)ethanol,isolated as the oxalate, m.p. 175°-6° C.

Analysis: Calc'd. for C₁₉ H₂₄ N₂ O₄.C₂ H₂ O₄ : C, 58.06; H, 6.03; N,6.45%: Found: C, 58.23; H, 6.43; N, 6.65%.

EXAMPLE III

A stirred mixture of 4-benzyloxyphenacyl bromide (18.3 g.),N-[2-(4-carbamoylmethylphenoxy)ethyl]benzylamine (17.0 g.), anhydroussodium carbonate (6.4 g.) and ethanol (200 ml.) was boiled under refluxfor 1 hour, then allowed to cool and filtered. Evaporation in vacuo ofthe filtrate afforded an oil which could not be induced to solidify. Itwas thus stirred with a mixture of sodium borohydride (2.4 g.), ethanol(100 ml.) and 1,4-dioxane (100 ml.) for 18 hours at room temperature.The resulting mixture was acidified with 50% aqueous acetic acid thenevaporated in vacuo to provide an oil which on trituration with 10%aqueous sodium carbonate solution, gave a white powder (17.3 g.).Crystallization of a sample (2.0 g.) from methanol furnishedDL-2-[N-benzyl-2-(4-carbamoylmethylphenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanolhydrate (0.9 g.), m.p. 105°-107° C.

Analysis: Calc'd. for C₃₂ H₃₆ N₂ O₅ : C, 72.70; H, 6.86; N, 5.30%:Found: C, 72.99; H, 6.86; N, 5.31%.

The previous product (15.3 g.) was hydrogenated over 10%palladium/charcoal (1.5 g.) in 50% aqueous acetic acid solution (100ml.) in a Parr hydrogenator at 15 p.s.i. and room temperature.Filtration of the resulting mixture followed by evaporation in vacuo ofthe filtrate gave an oil which was neutralized by addition of 10%aqueous sodium carbonate solution. The aqueous phase was decanted andthe residual oil treated with water in which it rapidly dissolved. Onstanding, the latter solution deposited a white solid; several morecrops were obtained by concentration of this solution, and also from thedecantate, to give a total yield of 6.9 g. Crystallization from methanolaffordedDL-2-[2-(4-carbamoylmethylphenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol(4.1 g.) m.p. 160°-161° C.

Analysis: Calc'd. for C₁₈ H₂₂ N₂ O₄ : C, 65.44; H, 6.71; N, 8.48%:Found: C, 65.85 H, 6.72; N, 8.36%.

EXAMPLE IV

(A) A stirred mixture of 3-benzyloxyphenacyl bromide (15.25 g.),N-[2-(4-sulfamoylphenoxy)ethyl]benzylamine (15.3 g.), anhydrous sodiumcarbonate (5.3 g.) and ethanol (200 ml.) was boiled under reflux for 1hour, then allowed to cool and filtered to remove the sediment ofinorganic salts. Evaporation in vacuo of the filtrate afforded a yellowsolid, which was distributed between water (500 ml.) and chloroform (400ml.). The layers, which initially coalesced into an emulsion, wereclarified by filtration through an anhydrous sodium carbonate pad. Thechloroform layer was separated, dried over anhydrous magnesium sulfateand evaporated in vacuo to afford a viscous yellow oil, which was foundto be very impure from thin layer chromatography evidence. Addition ofdiethyl ether, chilling, evaporation of the solvent and standing at roomtemperature eventually solidified the oil to a cake, which was crushed,washed with diethyl ether and dried, providing a cream-colored powder,yield 15.9 g., m.p. 110°-115° C.

(B) A solution of the crude product of (A) (13.25 g.) in 1:1 ethanol:1,4-dioxane (100 ml.) was added over one minute to a stirred suspensionof sodium borohydride (0.95 g.) in ethanol (100 ml.) at roomtemperature, and the mixture was stirred for a further 21 hours. Theresulting mixture was then acidified with glacial acetic acid, the wholethan being evaporated in vacuo to a tarry material to which was addedaqueous sodium carbonate solution. Water was added, and the resultingsolution extracted with chloroform. The layers, which initiallycoalesced into an emulsion, were clarified by filtration throughdiatomaceous earth. The chloroform layer was separated, dried overanhydrous magnesium sulfate and evaporated in vacuo to afford an oilwhich could not be induced to solidify despite trituration in 40°-60° C.petrol ether and diethyl ether with chilling.

(C) The crude product of the previous stage (13.2 g.) was hydrogenatedover 10% palladium/charcoal (1.5 g.) in glacial acetic acid (90 ml.) ina Parr hydrogenator at 15 p.s.i.. and room temperature. Filtration ofthe resulting mixture followed by evaporation in vacuo of the filtrategave an oil which was dissolved in ethanol (200 ml.). To the ethanolicsolution was added concentrated hydrochloric acid which resulted inprecipitation of a white crystalline solid, which, after concentrationby evaporation of the suspension to a volume of 50 ml., was collected byfiltration and dried. It was then dissolved in a boilingethanol/methanol mixture, the solution filtered, and the filtratechilled and diluted with diethyl ether. The resultant precipitate ofwhite powder was collected by filtration and dried. The product,DL-2-[2-(4-sulfamoylphenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanolhydrochloride (5.95 g.) melted at 184° C. with decomposition.

Analysis: Calc'd. for C₁₆ H₂₀ N₂ O₅ S.HCL: C, 49.42; H, 5.44; N, 7.21%:Found: C, 49.33; H, 5.58; N, 7.14%.

The following compounds have been prepared, using the method of ExamplesIII and IV, from the appropriate starting materials.

The compounds of Examples XV, XVI and XVII were produced according tothe method of Examples III and IV but omitting the sodium borohydridereduction and effecting the hydrogenation of the carbonyl intermediateat a pressure of about 1000 p.s.i, and at room temperature in thepresence of palladium/charcoal catalyst.

    __________________________________________________________________________     ##STR19##                                                                                                           Analysis %                                                                    (calculated in                                                Position of                                                                          Salt/Free Base                                                                         brackets)                              EXAMPLE                                                                              R.sup.2                                                                           R.sup.3  R.sup.4                                                                          HO     m.p. ° C                                                                        C   H  N                               __________________________________________________________________________    V      H   4-CONH.sub.2                                                                           H  4-     Free base                                                                              64.56                                                                             6.27                                                                             8.86                                                          193-5°                                                                          (64.54                                                                            6.37                                                                             8.86)                           VI     H   4-NHCOCH.sub.3                                                                         CH.sub.3                                                                         4-     Hydrochloride                                                                          59.59                                                                             6.47                                                                             7.39                                                          213-6° *                                                                        (59.92                                                                            6.62                                                                             7.36)                           VII    H   4-CONH.sub.2                                                                           CH.sub.3                                                                         4-     Free base                                                                              65.41                                                                             6.63                                                                             8.25                                                          193-6° *                                                                        (65.44                                                                            6.71                                                                             8.48)                           VIII   H   4-NHCOCH.sub.3                                                                         H  3-     Hydrochloride                                                                          54.56                                                                             6.01                                                                             7.25                                                          sesquihydrate                                                                          (54.89                                                                            6.64                                                                             7.11)                                                         196-8°                                   IX     H   4-NHCOCH.sub.3                                                                         H  4-     Hydrochloride                                                                          58.52                                                                             6.46                                                                             7.68                                                          211-2°                                                                          (58.92                                                                            6.32                                                                             7.64)                           X      H   4-CH.sub.2 CONH.sub.2                                                                  CH.sub.3                                                                         4-     Free base                                                                              66.34                                                                             7.21                                                                             7.88                                                          132-4° *                                                                        (66.26                                                                            7.02                                                                             8.13)                           XI     H   4-NHCOCH.sub.2 CH.sub.3                                                                H  4-     Hydrochloride                                                                          59.68                                                                             6.59                                                                             7.31                                                          192-3°                                                                          (59.90                                                                            6.61                                                                             7.35)                           XII    4-CH.sub.3                                                                        2-CONH.sub.2                                                                           H  4-     Hydrochloride                                                                          58.88                                                                             6.43                                                                             7.77                                                          160-2°                                                                          (58.94                                                                            6.32                                                                             7.64)                           XIII   H   4-NHSO.sub.2 CH.sub.3                                                                  H  4-     Free base                                                                              56.08                                                                             5.85                                                                             7.48                                                          151-3°                                                                          (55.72                                                                            6.05                                                                             7.64)                           XIV    H   2-NHCOCH.sub.3                                                                         H  4-     Acetate  61.77                                                                             6.61                                                                             7.14                                                          166-7°                                                                          (61.52                                                                            6.71                                                                             7.18)                           XV     H   4-CONH.sub.2                                                                           CH.sub.3                                                                         4-     Free base                                                                              65.58                                                                             6.74                                                                             8.28                                                          202-4° **                                                                       (65.44                                                                            6.71                                                                             8.48)                           XVI    H   4-NHCOCH.sub.3                                                                         CH.sub.3                                                                         4-     Free base                                                                              66.43                                                                             7.03                                                                             8.01                                                          169-170° **                                                                     (66.26                                                                            7.02                                                                             8.13)                           XVII   H   4-CH.sub.2 CONH.sub.2                                                                  CH.sub.3                                                                         4-     Free base                                                                              66.36                                                                             6.98                                                                             8.19                                                          162-4° **                                                                       (66.26                                                                            7.02                                                                             8.13)                           XVIII  H   4-CH.sub.2 NHCOCH.sub.3                                                                H  4-     Free base                                                                              66.13                                                                             7.06                                                                             7.84                                                          147.5-148.5°                                                                    (66.26                                                                            7.02                                                                             8.13)                           __________________________________________________________________________      * threo isomers                                                              ** erythro isomers                                                       

EXAMPLE XIX

A mixture of 3,4-dibenzyloxyphenacyl bromide (8.2 g.),N-[2-(4-carbamoxylphenoxy)ethyl]benzylamine (5.4 g.) anhydrous sodiumcarbonate (2.1 g.) and ethanol (250 ml.) was boiled under reflux for 3hours, then filtered hot to remove the inorganic sediment and cooled to0° C. The resultant precipitated solid was collected by filtration,washed with diethyl ether and dried. The product,N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-carbamoylphenoxy)ethylamine(11.0 g.) melted at 140°-2° C.

Analysis: Calc'd. for C₃₈ H₃₆ N₂ O₅.0.5H₂ O: C, 74.88; H, 6.1; N, 4.60%.Found: C, 75.83; H, 5.87; N, 4.38%.

Sodium borohydride (4.0 g.) was dissolved in the minimum volume of waterand 2 drops of 5N sodium hydroxide solution were added. The solution wasadded to a suspension of the previous product (10.5 g.) in ethanol (300ml.) and the mixture stirred for 3 hours at room temperature, thengently warmed on a steam bath to achieve complete solution, and cooledagain, stirring then being continued at room temperature for a further36 hours. The solution was acidified by addition of a few drops ofglacial acetic acid and the volume of the suspension reduced by onehalf. Water (300 ml.) was added and the solid collected by filtration,washed in boiling water and dried to affordDL-2-[N-benzyl-2-(4-carbamoylphenoxy)ethylamino]-1-(3,4-dibenzyloxyphenyl)ethanol(10.1 g.), m.p. 110°-1° C.

Analysis: Calc'd. for C₃₈ H₃₈ N₂ O₅.0.5H₂ O: C, 74.60; H, 6.43; N,4.58%. Found: C, 74.61; H, 5.80; N, 4.32%.

The previous product (6.0 g) was hydrogenated over 10%palladium/charcoal (600 mg.) in 50% aqueous acetic acid solution (60ml.) in a Parr hydrogenator at 15. p.s.i. and room temperature.Filtration of the resulting mixture followed by evaporation in vacuo ofthe filtrate at less than 40° C. gave a brown syrup. Addition of anisopropanol/methanol mixture gave a solution and a black solid. Thelatter was removed by filtration and to the filtrate was added etherealhydrogen chloride, which produced a gum. Decantation followed bytrituration of the gum in methanol afforded a pink solid A (0.4 g.). Thedecanted isopropanol/methanol/diethyl ether solution was concentrated byevaporation in vacuo, which resulted in precipitation of some more pinksolid B (1.3 g.). The filtrates from the collections of solids A and Bwere combined and treated with a small volume of diethyl ether. Coolingof this solution at 0° C. produced a third crop of crystals, solid C(0.2 g.). Solids A, B and C were combined and dissolved in the minimumvolume of methanol, to which was added an approximately equal volume ofisopropanol. The solution was concentrated by evaporation until suchtime as formation of crystals was first observed, after which thesolution was cooled at 0° C. during which time more crystallizationoccurred. The product, collected by filtration and dried, consisted ofDL-2-[2-(4-carbamoylphenoxyethylamino]-1-(3,4-dihydroxyphenyl)ethanolhydrochloride (1.05 g.), m.p. 184° C. with decomposition.

Analysis: Calc'd. for C₁₇ H₂₀ N₂ O₅.HCl: C, 55.36; H, 5.74; N, 7.60%.Found: C, 54.98; H, 5.87; N, 7.34%.

EXAMPLE XX

A mixture of 3,4-dibenzyloxyphenacyl bromide (32.8 g.),N-[2-(4-acetamidophenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodiumcarbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 2hours, then filtered hot to remove the inorganic sediment and evaporatedin vacuo to afford a thick syrup. The latter was dissolved in hotisopropanol and the solution cooled, the precipitated solid then beingcollected by filtration. To a hot solution of the solid in freshisopropanol were added a few milliliters of ethyl acetate, and thesolution was then allowed to cool to room temperature. The crystallizedsolid was collected by filtration, washed in diethyl ether and dried.Recrystallization from an isopropanol/ethyl acetate mixture affordedN-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-acetamidophenoxy)ethylamine(32.8 g.), m.p. 104°-6° C.

Analysis: Calc'd. for C₃₉ H₃₈ N₂ O₅ : C, 76.20; H, 6.23; N, 4.56%.Found: C, 75.93; H, 6.28; N, 4.13%.

Sodium borohydride (12.0 g.) was dissolved in water (40 ml.) and 8 dropsof 5N sodium hydroxide solution were added. The solution was added to asuspension of the previous product (32.8 g) in ethanol (800 ml.) and themixture gently warmed on a steam bath to achieve complete solution.After removal of the steam bath, the solution was stirred for 10 minutesand poured into water containing a little acetic acid, which resulted inthe precipitation of a gummy solid. The latter was extracted intochloroform and the chloroform solution separated and evaporated down invacuo to give a syrup (20.4 g.), which consisted of crudeDL-2-[N-benzyl-2-(4-acetamidophenoxy)ethylamino]-1-(3,4-dibenzyloxyphenyl)ethanol.

The previous product (20.0 g.) was hydrogenated over 10%palladium/charcoal (2.0 g.) in 50% aqueous acetic acid solution (200ml.) in a Parr hydrogenator at 15 p.s.i. and room temperature.Filtration of the resulting mixture followed by evaporation in vacuo ofthe filtrate at less than 40° C. gave a syrup, which was subsequentlytaken up into toluene and the solution evaporated down, this processbeing repeated until the residue consisted of a pink solid. The latterwas dissolved in hot methanol and isopropanol added to the solution.After removal of excess methanol by evaporation in vacuo, a precipitateformed, and this was collected by filtration and dried (yield 11.2 g.;m.p. 150° C. with decomposition). Recrystallization from ethanolafforded 7.1 g. of crystalline material, m.p. 165° C. withdecomposition. The filtrate from the crystallization inisopropanol/methanol was treated with ethereal hydrogen chloride, whichresulted in precipitation of white crystals (4.6 g.) ofDL-2-[2-(4-acetamidophenoxy)ethylamino]-1-(3,4-dihydroxyphenyl)ethanolhydrochloride hemihydrate, m.p. 176° C. with decomposition.

Analysis: Calc'd. for C₁₈ H₂₂ N₂ O₅.HCl.0.5H₂ O: C, 55.16; H, 5.92; N,7.15%. Found: C, 55.27; H, 6.21; N, 6.88%.

EXAMPLE XXI

Also prepared by the method described in Examples XIX and XX from3,4-dibenzyloxyphenacyl bromide andN-[2-(4-carbamoylmethylphenoxy)ethyl]benzylamine wasDL-2-[2-(4-carbamoylmethylphenoxy)ethylamino]-1-(3,4-dihydroxyphenyl)ethanol hydrochloride, m.p. 224°-8° C.

Analysis: Calc'd. for C₁₈ H₂₂ N₂ O₅ HCl: C, 56.47; H, 6.05; N, 7.32%.Found: C, 56.49; H, 6.04; N, 7.51%.

EXAMPLE XXII

A mixture 3,4-dibenzyloxyphenacyl bromide (32.8 g.),N-[2-(4-carbamoylmethylphenoxy)ethyl]benzylamine (22.8 g.), anhydroussodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under refluxfor 3 hours, then filtered hot to remove the inorganic sediment andevaporated in vacuo to afford a thick syrup. The latter was crystallizedupon trituration in diethyl ether and a sample of the resultant solidwas recrystallized from ethanol to giveN-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-carbamoylmethylphenoxy)ethylamine,m.p. 99°-101° C.

Analysis: Calc'd. for C₃₉ H₃₈ N₂ O₅.0.5H₂ O: C, 75.10; H, 6.30; N,4.49%. Found: C, 75.42; H, 6.22; N, 4.17%.

The previous product (7.0 g.) was hydrogenated over 10%palladium/charcoal (700 mg.) in 50% aqueous acetic acid solution (70 ml)in a Parr hydrogenator at 15 p.s.i. and room temperature. Filtration ofthe resulting mixture was followed by evaporation in vacuo of thefiltrate to dryness, the crude product then being azeotroped in turnwith water and toluene. The resulting syrup was dissolved in methanol,and ethereal hydrogen chloride was slowly added to the methanolicsolution, yielding a precipitate of fawn crystals (4.0 g) which wassubsequently collected by filtration and recrystallized from water witha little concentrated hydrochloric acid added. The crystals werecollected by filtration and dried to give2-(4-carbamoylmethyl-phenoxy)-N-(3,4-dihydroxybenzoyl)methyl ethylaminehydrochloride (3.0 g.), m.p. 240° C. with decomposition.

Analysis: Calc'd. for C₁₈ H₂₀ N₂ O₅.HCl: C, 56.78; H, 5.55; N, 7.36%.Found: C, 57.01; H, 5.73; N, 7.22%.

EXAMPLE XXIII

Also prepared by the method described in Example XXII from3,4-dibenzyloxyphenacyl bromide andN-[2-(2-carbamoyl-4-methylphenoxy)-ethyl]benzylamine was2-(2-carbamoyl-4-methylphenoxy)-N-(3,4-dihydroxybenzoyl)methylethylamine hydrochloride hemihydrate, m.p. 180° C., with decompositionbetween 218°-223° C.

Analysis: Calc'd. for C₁₈ H₂₀ N₂ O₅.HCl.0.5H₂ O: C, 55.44; H, 5.69; N,7.19%. Found: C, 55.62; H, 5.62; N, 7.37%.

EXAMPLE XXIV

A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine (13.6 g.),2-(4-sulfamoylphenoxy)ethyl chloride (4.8 g.) and dry xylene (50 ml.)was boiled under reflux for 12 hours. The solution was cooled and theprecipitated solid removed by filtration, the filtrate then beingevaporated in vacuo to dryness and taken up into diethyl ether.Insoluble material was removed from the ethereal solution by filtration,and the filtrate treated with ethereal hydrogen chloride, which resultedin the precipitation of a yellow solid. The latter was collected byfiltration and recrystallized from a methanol/isopropanol mixture givingN-[2-(3,4-dibenzyloxyphenyl)ethyl]-N-[2-(4-sulfamoylphenoxy) ethyl]benzylamine hydrochloride (5.8 g.), m.p. 178°-181° C.

Analysis: Calc'd. for C₃₇ H₃₈ N₂ O₅ S.HCl: C, 67.40; H, 5.96; N, 4.25%.Found: C, 67.62; H, 6.03; N, 4.26%.

The previous product (5.7 g.) was hydrogenated over 10%palladium/charcoal in glacial acetic acid in a Parr hydrogenator at 15p.s.i. and room temperature. The catalyst was removed by filtration andthe filtrate evaporated in vacuo to a gum, which was triturated in alittle acetone. The resulting grey solid was filtered off, andrecrystallized from 5N hydrochloric acid givingN-[2-(3,4-dihydroxyphenyl)ethyl]-2-(4-sulfamoylphenoxy)ethylaminehydrochloride as pale mauve crystals, m.p. 245°-7° C.

Analysis: Calc'd. for C₁₆ H₂₀ N₂ O₅ S.HCl: C, 49.40; H, 5.44; N, 7.20%.Found: C, 49.39; H, 5.41; N 7.31%.

The following compounds have been prepared, using the method of ExampleXXIV from the appropriate starting materials.

    ______________________________________                                         ##STR20##                                                                                         Analysis %                                                             Salt   (calculated in brackets)                                 Ex.   R.sup.2 R.sup.3   m.p. ° C                                                                      C     H     N                                  ______________________________________                                        XXV  4-CH.sub.3                                                                             2-CONH.sub.2                                                                            Hydro- 58.66 6.33  7.47                                                       chloride                                                                             (58.93                                                                              6.32  7.64)                                                      200-202°                                       XXVI H        4-CONH.sub.2                                                                            Hydro- 57.46 5.90  8.02                                                       chloride                                                                             (57.87                                                                              5.71  7.94                                                       241-3°                                         ______________________________________                                    

EXAMPLE XXVII

A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine (12.0 g.),2-(4-acetamidophenoxy)ethyl chloride (3.1 g.) and dry dimethylformamide(10 ml.) was boiled under reflux for 10 hours. The solution was cooled,more dimethylformamide (15 ml.) added, and the precipitated solidremoved by filtration. The filtrate was evaporated in vacuo to drynessand the resultant solid stirred in chloroform, after which undissolvedmaterial was removed by filtration and the filtrate was evaporated invacuo to dryness to give the crude product,N-[2-(3,4-dibenzyloxyphenyl)ethyl]-N-[2-(4-acetamidophenoxy)ethyl]benzylamine.

The previous product was hydrogenated over 10% palladium/charcoal inaqueous acetic acid with a few drops of concentrated hydrochloric acidadded in a Parr hydrogenator at 15 p.s.i. and room temperature. Thecatalyst was removed by filtration and the filtrate evaporated in vacuoto a gummy solid. The latter was crystallized from dilute hydrochloricacid, givingN-[2-(3,4-dihydroxyphenyl)ethyl]-2-(4-acetamidophenoxy)ethylaminehydrochloride (2.5 g.) m.p. 219°-221° C.

Analysis: Calc'd. for C₁₈ H₂₂ N₂ O₄.HCl: C, 58.93; H, 6.32; N, 7.64%.Found: C, 58.97; H, 6.26; N, 7.90%.

The following compounds have been prepared, using the method of ExampleXXVII, from the appropriate starting materials.

    __________________________________________________________________________     ##STR21##                                                                                                Analysis % -Salt (calculated in brackets)         EXAMPLE                                                                              R.sup.2                                                                            R.sup.3 m.p. ° C.                                                                      C   H   N                                         __________________________________________________________________________    XXVIII 2-OCH.sub.3                                                                        4-CONH.sub.2                                                                          Hydrochloride                                                                         55.80                                                                             6.22                                                                              7.09                                                          0.25 hydrate                                                                          (55.82                                                                            6.05                                                                              7.23)                                                         168-171°                                           XXIX   H    3-CONH.sub.2                                                                          Hydrochloride                                                                         57.97                                                                             5.92                                                                              7.79                                                          211-4°                                                                         (57.87                                                                            5.71                                                                              7.94)                                     XXX    H    4-CH.sub.2 CONH.sub.2                                                                 Hydrochloride                                                                         58.83                                                                             6.35                                                                              7.45                                                          219-221°                                                                       (58.93                                                                            6.32                                                                              7.64)                                     __________________________________________________________________________

EXAMPLE XXXI

A mixture of 2-(4-hydroxyphenyl)ethylamine (5.6 g.),2-(4-carbamoylphenoxy) ethyl chloride (4.0 g.) and dimethylformamide (25ml.) was heated at 140° C for 4 hours. After cooling to roomtemperature, the mixture was poured into water and the resultantprecipitated solid was collected by filtration, washed in turn withwater, acetone and diethyl ether, and finally dried. The product,N-[2-(4-hydroxyphenyl)ethyl]-2-(4-carbamoylphenoxy)ethylaminehydrochloride melted with decomposition at 284° C.

Analysis: Calc'd. for C₁₇ H₂₀ N₂ O₃.HCl: C, 60.62; H, 6.28; N, 8.32%.Found: C, 60.41; H, 6.33; N, 8.56%.

EXAMPLE XXXII

Also prepared by the method described in Example XXXI from2-(4-hydroxyphenyl)ethylamine and 2-(4-acetamidophenoxy)ethyl chloridewas N-[2-(4-hydroxyphenyl)ethyl]-2-(4-acetamidophenoxy)ethylaminehydrochloride, m.p. 275°-7° C.

Analysis: Calc'd. for C₁₈ H₂₂ N₂ O₃.HCl: C, 61.62; H, 6.61; N, 7.99%.Found: C, 61.51; H, 6.64; N, 8.01%.

EXAMPLE XXXIII

(A) A stirred suspension of 4-benzyloxyphenacyl bromide (30.5 g.)N-benzyl-2-(4-nitrophenoxy)ethylamine hydrochloride (30.85 g.) andanhydrous sodium carbonate (21.2 g.) in ethanol (300 ml.) was boiledunder reflux for 11/2 hours. The mixture was then filtered while stillhot to remove sodium salts and the ethanolic filtrate evaporated invacuo to a brown oil (48.7 g.), consisting of crudeN-benzyl-N-(4-benzyloxybenzoyl)methyl-2-(4-nitrophenoxy) ethylamine.

(B) Addition of 1,4-dioxane (150 ml.) to the product of (A) causedprecipitation of some white solid. The latter was removed by filtration,and the dark brown filtrate added over 5 minutes to a stirred suspensionof sodium borohydride (3.8 g.) in ethanol (100 ml.) at room temperature.Stirring was continued for 20 hours, after which the mixture wasacidified with glacial acetic acid, diluted by addition of water andbasified with aqueous sodium carbonate solution. The solution wasextracted with chloroform (2 × 200 ml.) and the chloroform solutionsseparated, combined, dried over anhydrous magnesium sulfate andevaporated in vacuo to a brown oil (41.8 g.), consisting of crudeDL-2-[N-benzyl-2-(4-nitrophenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanol.

(C) The crude product of (B), dissolved in a mixture of ethanol (150ml.) and 1,4-dioxane (50 ml.), was submitted to hydrogenation at 50p.s.i. and room temperature in the presence of Raney nickel catalyst.Removal of catalyst by filtration followed by evaporation of thefiltrate in vacuo yielded crudeDL-2-[N-benzyl-2-(4-aminophenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanol(37.85 g.) as a dark brown tar.

(D) A solution of methyl isocyanate (2.85 g.) in chloroform (25 ml.) wasadded over 1/2 minute to a stirred solution of the product of (C) (23.4g.) in chloroform (100 ml.). Stirring at room temperature was continuedfor 21/2 hours, after which the solution was evaporated in vacuo to abrown oil. A small sample of the latter yielded a white powder ontrituration in 40°-60° petrol ether/diethyl ether/acetonitrile, and theremaining oil was triturated in 40°-60° petrol ether, the mixture beingseeded with the foregoing white powder to yield, on standing, a greysolid mass. The latter was crushed and dried, and consisted of crudeDL-2-[N-benzyl-2-(4-{3-methylureido}phenoxy)ethylamino]-1-(4-benzoyloxphenyl)ethanol. A small portion wascrystallized from acetonitrile to yield crystals, m.p. 113°-116° C.

Analysis: Calc'd. for C₃₂ H₃₅ N₃ O₄ : C, 73.12; H, 6.71; N, 8.00. Found:C, 72.82; H, 6.59; N, 8.01.

(E) The product of (D) (22.0 g.) dissolved in glacial acetic acid washydrogenated at 15 p.s.i. and room temperature in the presence ofpalladium/charcoal catalyst. The catalyst was then removed by filtrationand the filtrate treated with concentrated hydrochloric acid (4 ml.˜1equivalent) and evaporated in vacuo to a green oil, which was trituratedin diethyl ether/isopropanol to afford a grey tar. Trituration of thelatter in acetonitrile (100 ml.) yielded an off-white powder (12.75 g.),which was subsequently dissolved in the minimum amount of warm water,the solution then being basified with aqueous sodium carbonate solution.The aqueous phase was decanted from the precipitated green tar and thelatter triturated in turn in diethyl ether and acetone. Successivetriturations in fresh amounts of acetonitrile induced solidification togive a cream-colored product (8.45 g.). Crystallization fromethanol/water afforded a cream-colored solid, m.p. 155°-160° C withdecomposition. A silver nitrate test on the product indicated thepresence of halide and so it was inferred that the product wascontaminated with the hydrochloride salt. The aqueous ethanol filtratewas evaporated in vacuo to dryness and the residue combined with thecrystallized solid, m.p. 155°-160° C., and the whole treated with warmaqueous saturated sodium carbonate solution to convert it to the freebase. Resulting was a fawn powder (6.0 g.) which was crystallized fromethanol to provide fawn crystals (3.7 g.), m.p. 164°-166° C. withdecomposition. A final recrystallization from an ethanol/methanolmixture yielded light fawn crystals (2.85 g.) ofDL-1-(4-hydroxyphenyl)-2-[2-(4-{3-methylureido}phenoxy)ethylamino]ethanol, m.p. 165°-6° C. with decomposition.

Analysis: Calc'd. for C₁₈ H₂₃ N₃ O₄ : C, 62.59; H, 6.71; N, 12.17%.Found: C, 62.86; H, 6.80; N, 11.88%.

EXAMPLE XXXIV

Ethyl chloroformate (5.45 g.) was added dropwise over 2- 3 minutes to astirred, warm suspension ofDL-2-[N-benzyl-2-(4-aminophenoxy)ethylamino]-1-(4-benzyloxyyphenyl)ethanol(23.4 g) (prepared as described in Example XXXIII (A), (B) and (C)) andanhydrous potassium carbonate (6.9 g.) in ethanol (150 ml.) and thestirred mixture was boiled under reflux for 1/2 hour. The suspension wasthen filtered hot to remove off-white solid and the filtrate evaporatedin vacuo to a brown tar (27.0 g.) consisting of crudeDL-2-[N-benzyl-2-(4-ethoxycarbonylaminophenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanol hydrochloride.

The previous crude product (27.0 g.) was dissolved in 1:1 glacial aceticacid: water (240 ml.) and hydrogenated at 15 p.s.i. and room temperatureover 10% palladium/charcoal catalyst. The catalyst and some accompanyinggrey solid (independently shown to consist in all probability of themono-O-benzyl compound mainly) were filtered off, and the yellow aqueousacetic acid filtrate evaporated in vacuo at 40° C. to give a fawn gum,which was triturated in diethyl ether (2 × 250 ml.), the resultant fawnsolid then being collected by filtration, dried at 80° C. in vacuo andcrystallized from ethanol. The product consisted of off-white crystals(2.25 g.) of DL-2-[2 -(4-ethoxycarbonylaminophenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol hydrochloride, which melted withdecomposition in the range 187°-9° C. to an opaque melt, the latterdecomposing further with clarification in the range 225°-230° C.

Analysis: Calc'd. for C₁₉ H₂₄ N₂ O₅.HCl: C, 57.49; H, 6.35; N, 7.06%.Found: C, 57.64; H, 6.06; N, 6.94%.

EXAMPLE XXXV

90% Aqueous formic acid solution (4.3 ml.) was added dropwise over 2-3minutes to a stirred, warm solution ofDL-2-[N-benzyl-2-(4-aminophenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanol(23.4 g.) (prepared as described in Example XXXIII (A), (B) and (C) inbenzene (150 ml.) and the stirred solution was boiled under reflux for 1hour. Evaporation of the solution, which consisted of two liquid layers,in vacuo afforded a brown oil, and this was then diluted with water (200ml.) and the pH adjusted to about 6.5 using saturated aqueous sodiumcarbonate solution. The solution was extracted with chloroform (2 × 100ml.), the chloroform layers then being separated, dried over anhydrousmagnesium sulfate and evaporated in vacuo to afford a brown tar (26.0g.), which consisted of crude DL-2-[N-benzyl-2 -(4-formamidophenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanol.

The previous crude product (26.0 g.) was dissolved in glacial aceticacid (120 ml.) and hydrogenated at 15 p.s.i. and room temperature over5% palladium/charcoal catalyst. Evaporation of the filtrate in vacuo at40° C. from the removal of catalyst yielded a brown tar, which wasazeotroped with benzene (2 × 100 ml.). To the resulting brown tar wasadded water (150 ml) and the pH of the solution, containing suspendedwhite solid, was adjusted from about 4.5 to about 9.5, at which pointthe solution contained a fawn precipitate. The residual tar wasconverted to solid by stirring, the whole solid then being collected byfiltration and recrystallized twice from ethanol to give fawn crystals(6.55 g.) ofDL-1-(4-benzyloxyphenyl)-2-[2-(4-formamidophenoxy)ethylamino]ethanol,m.p. 151.5°- 152.5° C.

Analysis: Calc'd. for C₂₄ H₂₆ N₂ O₄ : C, 70.91; H, 6.45; N, 6.89%,Found: C, 70.56; H, 6.45; N, 6.27%.

The previous product (4.06 g.) was dissolved in glacial acetic acid (60ml.) and hydrogenated at 15 p.s.i. and room temperature over 10%palladium/charcoal catalyst. Removal of the catalyst by filtration,followed by evaporation in vacuo of the filtrate afforded a brown oil,to which was added saturated aqueous sodium carbonate solution. Theresultant gum was solididied by trituration in ethanol, and the solidcollected by filtration and crystallized from ethanol to yield off-whitecrystals (2.3 g.) ofDL-2-[2-(4-formamidophenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol, m.p.164°-5° C. with decomposition which was found from nuclear magneticresonance spectroscopy to contain about 10% ethanol.

Analysis: Calc'd. for C₁₇ H₂₀ N₂ O₄ .0.1C₂ H₅ OH: C, 64.37; H, 6.47; N,8.73%, Found: C, 64.69; H, 6.52; N, 8.92%.

What is claimed is:
 1. A compound of the formula: ##STR22## wherein Rand R¹ are each hydrogen or hydroxy with the proviso that at least oneis hydroxy; R² is hydrogen, alkyl of from 1 to 4 carbon atoms or alkoxyof from 1 to 4 carbon atoms; R³ is formamido, acetamido, propionamido orcarbamoyl, any one of which may be separated from the phenyl ring by amethylene or ethylene group; R⁴ , R⁵ and R⁶ are each hydrogen or alkylof from 1 to 4 carbon atoms; X is oxygen, sulfur, imino or a directlink; Y is hydrogen and hydroxy, two hydrogens or oxygen; n is 1 to 3when X is other than a direct link and is 0 to 4 when X is a directlink; and the pharmaceutically-acceptable acid addition salts.
 2. Acompound of claim 1 wherein X is oxygen, n is 1 and Y is hydrogen andhydroxy, two hydrogens or oxygen.
 3. A compound of claim 1 wherein R⁶,R⁵ and R⁴ are each hydrogen.
 4. A compound of claim 1 wherein R¹ ishydroxy and R is hydrogen.
 5. A compound of claim 1 wherein R and R¹ areeach hydroxy.
 6. A compound of claim 1 wherein R is hydroxy and R¹ ishydrogen.
 7. A compund of claim 1 wherein R³ is carbamoyl, acetamido,formamido, or proponamido, separated from the phenyl ring by a methyleneor ethylene group.
 8. A compound of claim 1 wherein R² is hydrogen. 9.DL-2-[2-(4-(carbamoylphenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol andits pharmaceutically-acceptable acid addition salts. 10.DL-2-[2-(4-formamidophenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol andits pharmaceutically-acceptable acid addition salts. 11.DL-2-[2-(4-carbamoylmethylphenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol and its pharmaceutically-acceptable acid addition salts. 12.DL-2-[2-(4-acetamidophenoxy)ethylamino]-1-(4-hydroxyphenyl)ethanol andits pharmaceutically-acceptable acid addition salts.